This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background &Aims: The Gastrointestinal tract (GIT) is a major target of HIV/SIV infection. Although our understanding of HIV/SIV enteropathy has greatly improved, the recent discovery of miRNAs has added yet another novel and complex regulator of gene expression with potential roles in the molecular pathogenesis of this disorder. microRNAs (miRNAs) are genomically transcribed, ~21-23 nucleotide noncoding RNAs that are highly conserved and suppress gene expression by targeting mRNAs for translational repression or degradation. We investigated the contribution of 11 miRNAs to GIT disease and inflammation using the SIV-infected rhesus macaque model. Methods: Colon tissue was collected at necropsy from 10 SIV-infected (G1) with chronic diarrhea and 5 uninfected control macaques (G2). The contributions of miR-21, miR-125b, miR-132, miR-142-3p, miR-142-5p, miR-146a, miR-155, miR-203, miR-212, miR-223 and miR-338, previously known to be associated with inflammation were investigated using QRT-PCR, In situ hybridization/Immunofluorescence, histopathology and mass spectrometry. Results: All G1 macaques had chronic diarrhea, wasting and colitis. Significant to moderate increase in the expression of miR-142-3p, miR-142-5p (5-6-fold), miR-212 (3-fold), miR-21 (2-fold) was observed in the colon of G1 macaques compared to G2 animals. Interestingly, miR-125b and miR-203 were downregulated (2-3 fold) in G1 animals. No change in miR-132, miR-146a, miR-155 , miR-223 and miR-338 expression was observed between the groups. In situ hybridization using Locked-nucleic acid modified miR-212 probes revealed cytoplasmic and nuclear localization in the colonic epithelium and lamina propria cells (macrophages). Using mass spectrometry, we validated several predicted mRNA targets of miR-142-3p and miR-212 following over expression of both miRNAs in in vitro cultured primary intestinal macrophages. Conclusion: Our findings suggest that deregulation in cell/tissue-specific expression of miRNAs occurring in response to HIV/SIV infection may disrupt the functional relationship between the intestinal epithelium and the mucosal immune system causing alterations in intestinal structure and function.